Project Summery Overall Research Strategy: Traumatic brain injury (TBI) from open-field blast or repetitive mild head impact to human tau transgenic mice will induce Alzheimer-relevant, tau-dependent pathology, that can be rescued by suppression of tau expression or tau aggregation inhibitors. Blast-induced tau-related pathological changes will be analyzed in brains from veterans and mice exposed to blast, and biomarkers for TBI, chronic traumatic en- cephalopathy (CTE) and Alzheimer-pathology will be identified in mice and validated in humans. TBI caused by explosive weaponry is the most prominent type of injury that occurs in military personnel. Over 82% of combat- related TBIs are classified as mild TBIs (mTBI)?the ?signature injury? of recent wars. Service members with mTBI, often undetectable by conventional brain imaging techniques, do not realize they have sustained this injury. This ?invisible injury? can lead to the development of lifelong disabilities, including neuropsychiatric and/or neurodegenerative diseases, imposing socioeconomic burdens on patients, families, and society. To- date, our understanding of the mechanisms by which open-field low-intensity blast (LIB) causes mTBI and sub- sequent neurological deficits remains inadequate. Thus, there is an urgent need for investigation of LIB-in- duced pathogenesis using reliable and ?real world? animal models. Here, we have assembled a team of investi- gators with cross-disciplinary expertise and unique blast and in vivo imaging research facilities available at the Harry S. Truman Veterans Hospital and the affiliated University of Missouri. We have developed a platform us- ing pressure sensor instrumentations and high-speed cameras to reproduce and record open-field blast expo- sures with high-explosive velocity C4 detonation. Our preliminary studies show that LIB-exposed mice results in reduced locomotor/exploratory activity, but with no mortality or other impact/acceleration-mediated bodily injuries. Using transmission electron microscopy (TEM), we observed mitochondrial damage in cell bodies and defected myelin in selected brain areas. Further omics and biochemistry analyses indicated mitochondrial dys- function and increase in phospho-tau protein levels. We propose to test the hypothesis that LIB-induced neu- ropathology in a human tau transgenic mice is initiated by mitochondrial dysfunction associated with oxidative stress responses and bioenergetic impairment, which in turn, induces ultrastructural dam- ages and tau-related pathology leading to metabolic and behavioral deficits. This study will use the trans- genic mice expressing regulatable human tau (rTg-hTau) exposed either to a single or repetitive blasts in our well established platform, and investigate effects of mitochondrial dysfunction associated oxidative stress re- sponses in the mouse brain. Specifically, Aim-1 will evaluate effects of LIB-induced mTBI on ultrastructure in specific brain areas over time, assess behavioral changes, and determine metabolic profiles by PET/SPECT scanning using the rTg-hTau mice; Aim-2 will further characterize cell type involvement of ultrastructural changes and subcellular injuries using TEM combined with immunogold staining technique and immunohisto- chemistry; and Aim-3 will investigate underlying mechanism of mitochondrial dysfunction on mTBI pathogene- sis and evaluate whether the blast injury is affected by sex difference in rTg-hTau mice following LIB exposure to gain insights into its relationship with tau pathology. The results of this research will impact our understand- ing of tau-mediated pathogenesis of mTBI due to combat blast and provide mechanism for its prevention and treatment.